JP2006504639A - Pyrazol-3-one derivatives, methods for their preparation, and pharmaceutical compositions containing them - Google Patents

Abstract

Provided are pharmaceutical compositions comprising a pyrazol-3-one derivative of Formula 1 or a non-toxic salt thereof, a process for its preparation, and a derivative or non-toxic salt thereof as an active ingredient.

Description

TECHNICAL FIELD The present invention relates to pyrazol-3-one derivatives or non-toxic salts thereof, methods for preparing them, and pharmaceutical compositions containing these as active ingredients.

BACKGROUND ART Most nonsteroidal anti-inflammatory drugs play a role in reducing inflammation, pain, and fever by blocking an enzyme called cyclooxygenase or prostaglandin G / H synthase. It also inhibits uterine contractions caused by hormones and also inhibits the growth of several types of cancer. Cyclooxygenase-1 (COX-1) was first discovered in cattle. COX-1 is constitutively expressed in various cell types. Unlike COX-1, cyclooxygenase-2 (COX-2) is a recently discovered isoform of cyclooxygenase that can be easily induced by mitogens, endotoxins, hormones, growth factors, and cytokines.

  Prostaglandins are powerful mediators of pathological and physiological processes. COX-1 plays a physiologically important role in the release of endogenous prostaglandins, maintenance of gastrointestinal shape and function, and renal blood circulation. On the other hand, COX-2 is induced by inflammatory factors, hormones, growth factors, cytokines, and the like. Thus, unlike constitutive COX-1, COX-2 is involved in the pathological process of prostaglandins. Therefore, selective inhibitors of COX-2 have fewer side effects due to the mechanism of action than existing non-steroidal anti-inflammatory agents. In addition, they reduce inflammation, pain, fever, and inhibit uterine contractions and the growth of some types of cancer caused by hormones. In particular, it is effective in reducing side effects such as gastric toxicity and renal toxicity. Furthermore, they inhibit contraction of smooth muscle by inhibiting the synthesis of contractile prostanoids. Therefore, it helps prevent preterm birth, menstrual irregularities, asthma, and eosinophilic disease.

  Recently, non-steroidal anti-inflammatory drugs have been used in colorectal cancer (European Journal of Cancer, Vol 37, p2302, 2001), prostate cancer (Urology, Vol 58, p127, 2001), and dementia (Exp. Opin. Invest. Drugs, Vol. 9, p671, 2000).

  In addition, selective inhibitors of COX-2 are expected to be effective in the treatment of osteoporosis or glaucoma. The literature (John Vane, “Towards a Better Aspirin”, Nature, Vol. 367, pp 215-216, 1994; Bruno Battistini, Regina Botting, and YSBakhle, “COX- 1 and COX-2: Toward the Development of More Selective NSAIDs ”Drug News and Perspectives, Vol. 7, pp501-512, 1994; David B. Reitz and Karen Seibert,“ Selective Cyclooxygenase Inhibitors ”Annual Reports in Medicinal Chemistry, James A Bristol, Vol. 30, pp 179-188, 1995).

  Various selective COX-2 inhibitors with various structures are known. Among them, selective COX-2 inhibitors having a diaryl heterocyclic structure, that is, a tricyclic structure, have been widely studied as strong candidate substances. The diaryl heterocyclic structure has a central ring and a sulfonamido or methylsulfone group bonded to one aryl ring. The initial material of such a diaryl heterocyclic structure is Dup697 (Bioorganic & Medicinal Chemistry Letters, Vol 5, p2123, 1995). Later, SC-58635 having a pyrazole ring (Journal of Medicinal Chemistry, Vol 40, p1347, 1997) and MK-966 having a furanone ring (International Publication No. 95/00501) were discovered as derivatives of Dup697 It was done.

US Pat. No. 5,466,823 discloses celecoxib of formula 14 which is a selective COX-2 inhibitor. Celecoxib is a substituted pyrazolylbenzenesulfonamide derivative.

WO 95/00501 discloses another selective COX-2 inhibitor, rofecoxib of formula 15. Rofecoxib has a diaryl heterocyclic structure with a central furanone ring.

化学式14から16の選択的COX-2阻害剤は、既存の非ステロイド性抗炎症剤に比べて副作用が少なくかつ小さい、有効な炎症治療剤である。 US Pat. No. 5,633,272 discloses valdecoxib of formula 16. Valdecoxib has a phenylsulfonamide moiety with a central isoxazole ring.

The selective COX-2 inhibitors represented by Chemical Formulas 14 to 16 are effective anti-inflammatory agents with fewer side effects and smaller than existing non-steroidal anti-inflammatory agents.

DISCLOSURE OF THE INVENTION One aspect of the invention provides a pyrazol-3-one derivative of Formula 1 or a non-toxic salt thereof.

  Another aspect of the present invention provides a method for preparing a pyrazol-3-one derivative or a non-toxic salt thereof.

  Another aspect of the present invention provides a pharmaceutical composition comprising a pyrazol-3-one derivative or a non-toxic salt thereof as an active ingredient for the treatment of fever, pain, inflammation.

  Yet another aspect of the present invention provides a pharmaceutical composition comprising a pyrazol-3-one derivative or a non-toxic salt thereof as an active ingredient for the treatment of cancer and dementia.

式中、
R₁及びR₂はそれぞれ独立してC₁-C₃アルキル、アリール、または置換アリールを表し；
R₃はアミノまたはメチルを表し；
R₄及びR₅はそれぞれ独立して水素、C₁-C₃アルキル、ハロゲン、ハロゲンで置換されたメチル、C₁-C₃アルコキシ、シアノ、またはニトロを表す。 BEST MODE FOR CARRYING OUT THE INVENTION According to one aspect of the present invention, a pyrazol-3-one derivative represented by Chemical Formula 1 or a non-toxic salt thereof is provided.

Where
R ₁ and R ₂ each independently represent C ₁ -C ₃ alkyl, aryl, or substituted aryl;
R ₃ represents amino or methyl;
R ₄ and R ₅ each independently represent hydrogen, C ₁ -C ₃ alkyl, halogen, halogen-substituted methyl, C ₁ -C ₃ alkoxy, cyano, or nitro.

Preferably, R ₁ and R ₂ each independently represent C ₁ -C ₃ alkyl; R ₃ represents methyl; R ₄ and R ₅ each independently represent hydrogen, C ₁ -C ₃ alkyl, halogen, Or C ₁ -C ₃ alkoxy.

The positions of R ₄ and R ₅ are preferably the 3rd and 4th positions, the 2nd and 4th positions, the 3rd and 5th positions, or the 3rd and 2nd positions, and more preferably the 3rd and 4th positions, respectively. .

  The pyrazol-3-one derivative represented by Chemical Formula 1 may exist in the form of a non-toxic salt. The term “non-toxic salt” means pharmaceutically acceptable non-toxic salts, including organic and inorganic salts.

  Inorganic salts of pyrazol-3-one derivatives of Formula 1 include, but are not limited to, inorganic salts of aluminum, ammonium, calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium, or zinc. An inorganic salt of ammonium, calcium, potassium, or sodium is preferable.

  Organic salts of pyrazol-3-one derivatives of Formula 1 include primary, secondary or tertiary amines, naturally occurring substituted amines, organic amine salts of cyclic amines, or basic ion exchange resin salts. However, the present invention is not limited to this. Examples of basic ion exchange resin salts include arginine, betaine, caffeine, choline, N, N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl. Morpholine, N-ethylpiperidine, N-methylglucamine, glucamine, glucosamine, histidine, hydroamine, N- (2-hydroxyethyl) piperidine, N- (2-hydroxyethyl) pyrrolidine, isopropylamine, lysine, methylglucamine, Examples include, but are not limited to, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, and tromethamine.

  The pyrazol-3-one derivative of Formula 1 may exist in the form of an organic acid salt or an inorganic acid salt.

  Examples of organic or inorganic acid salts of pyrazol-3-one derivatives of Formula 1 include acetic acid, adipic acid, aspartic acid, 1,5-naphthalenedisulfonic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid. Acid, 1,2-ethanedisulfonic acid, ethanesulfonic acid, ethylenediaminetetraacetic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, hydroiodic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, apple Acid, mandelic acid, methanesulfonic acid, mucinic acid, 2-naphthalenedisulfonic acid, nitric acid, oxalic acid, pantothenic acid, phosphoric acid, pivalic acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid , P-toluenesulfonic acid, undecanoic acid, and salts of 10-undecenonic acid, but are not limited thereto. Preferred are salts of succinic acid, hydrobromic acid, hydrochloric acid, maleic acid, methanesulfonic acid, phosphoric acid, sulfuric acid or tartaric acid.

The pyrazol-3-one derivatives of the present invention are preferably:
5- (4-methanesulfonylphenyl) -4- (4-methoxyphenyl) -1,2-dimethyl-1,2-dihydropyrazol-3-one;
5- (4-methanesulfonylphenyl) -1,2-dimethyl-4-phenyl-1,2-dihydropyrazol-3-one;
5- (4-methanesulfonylphenyl) -1,2-dimethyl-4- (4-methylphenyl) -1,2-dihydropyrazol-3-one; and
4- (3,4-dichlorophenyl) -5- (4-methanesulfonylphenyl) -1,2-dimethyl-1,2-dihydropyrazol-3-one.

式中、R₃、R₄、及びR₅は化学式1で定義される通りであり、R₆はC₁-C₃アルキルを表す。 According to another aspect of the present invention, a propionic acid derivative of Formula 4 is provided as a synthetic intermediate of the pyrazol-3-one derivative of Formula 1.

In the formula, R ₃ , R ₄ and R ₅ are as defined in Chemical Formula 1, and R ₆ represents C ₁ -C ₃ alkyl.

式中、R₁及びR₂は化学式1で定義される通りである。 According to another aspect of the present invention, there is provided a process for preparing a pyrazol-3-one derivative of Formula 1 or a non-toxic salt thereof, comprising the step of reacting a hydrazine derivative of Formula 5 with a propionic acid derivative of Formula 4. The

In the formula, R ₁ and R ₂ are as defined in Chemical Formula 1.

  The reaction is preferably carried out in a solvent that can be separated from the water produced during the reaction by a Dean-Stark trap apparatus. Examples of the solvent include, but are not limited to, benzene, toluene, xylene and the like. Most preferred is the use of toluene.

  The reaction is preferably performed by heating the reaction product to the boiling point of the solvent to complete the reaction. More preferably, toluene is used as a solvent and the reaction is heated to the boiling point of toluene and refluxed to complete the reaction.

  Separation and purification of the reaction product can be performed by concentration, extraction, or other processes commonly used in organic synthesis processes, and optionally by silica gel column chromatography.

式中、R₃、R₄、及びR₅は化学式1で定義される通りであり、R₆はC₁-C₃アルキルである。 The propionic acid derivative of Chemical Formula 4 can be prepared by reacting a sulfonylbenzoic acid derivative of Chemical Formula 2 with a phenyl acetate derivative of Chemical Formula 3 in the presence of a base.

Wherein R ₃ , R ₄ , and R ₅ are as defined in Chemical Formula 1, and R ₆ is C ₁ -C ₃ alkyl.

  Examples of the base include sodium hydride, potassium carbonate, and potassium hydroxide. Preferably, sodium hydride is used.

  According to another aspect of the present invention, there is a therapeutically effective amount of a pyrazol-3-one derivative of Formula 1 or a non-toxic salt thereof as an active ingredient and a pharmaceutically acceptable carrier for fever, pain, inflammation. Pharmaceutical compositions for treatment are provided.

  A pharmaceutical composition comprises a compound of Formula 1 or a non-toxic salt thereof when it is a selective inhibitor of cyclooxygenase-2. Therefore, the pharmaceutical composition can be used as an antipyretic, analgesic or anti-inflammatory agent with reduced side effects.

  Conventional non-steroidal anti-inflammatory agents non-selectively inhibit the prostaglandin synthases cyclooxygenase-1 and cyclooxygenase-2. Therefore, various side effects can occur.

  In contrast, the compound of Formula 1 and non-toxic salts thereof selectively inhibit cyclooxygenase-2. Therefore, the side effects of conventional non-steroidal antipyretic agents, analgesics, and anti-inflammatory agents can be reduced.

  The pharmaceutical composition of the present invention comprises a compound of formula 1 and / or a non-toxic salt thereof, and a pharmaceutically acceptable carrier or excipient. Therefore, the pharmaceutical composition can be used as an alternative to conventional non-steroidal anti-inflammatory agents. In particular, by reducing the side effects of conventional non-steroidal antipyretic agents, analgesics, and anti-inflammatory agents, the pharmaceutical composition of the present invention has peptic ulcer, gastritis, localized enteritis, ulcerative colitis, diverticulitis, Useful for patients with gastric bleeding and hypoprothrombinemia.

  The pharmaceutical composition of the present invention can be used for all inflammatory diseases associated with pathological prostaglandins, and is particularly useful for osteoarthritis and rheumatoid arthritis requiring high doses of nonsteroidal anti-inflammatory agents. is there.

  The pharmaceutical composition of the present invention can be administered in the form of an adult dose of 50 mg / kg / day to 400 mg / kg / day of the compound of formula 1. The appropriate dose is determined according to the severity of the disease.

  According to yet another aspect of the present invention, a medicament for the treatment of cancer and dementia comprising a therapeutically effective amount of a pyrazol-3-one derivative of formula 1 or a non-toxic salt thereof, and a pharmaceutically acceptable carrier. A functional composition is provided.

  Recently, non-steroidal anti-inflammatory drugs have been used in colorectal cancer (European Journal of Cancer, Vol 37, p2302, 2001), prostate cancer (Urology, Vol 58, p127, 2001), and dementia (Exp. Opin. Invest. Drugs, Vol. 9, p671, 2000). Accordingly, the pharmaceutical compositions of the invention that are non-steroidal anti-inflammatory agents can also be used for the treatment of these diseases.

  The pharmaceutical composition of the present invention can be administered in the form of an adult dose of 50 mg / kg / day to 400 mg / kg / day of a compound of Formula 1 or a non-toxic salt thereof, the appropriate dose depending on the severity of the disease It is determined.

  The pharmaceutical composition of the present invention comprises tablets, effervescent tablets, capsules, granules, powders, sustained release tablets, sustained release capsules (single unit formulation and multiple unit formulation). ), Intravenous and intramuscular solutions, infusions, suspensions, suppositories, or other suitable dosage forms.

  Sustained release pharmaceutical dosage forms comprise the active ingredient with or without an initial loading dose. They are complete or partial sustained release pharmaceutical dosage forms that release the active ingredients in a controlled manner.

  Preferably, the pharmaceutical composition is administered orally.

  The pharmaceutical composition further comprises a pharmaceutically effective amount of pharmaceutically acceptable excipients and / or diluents and / or adjuvants.

  Examples of excipients and adjuvants include gelatin, natural sugars such as sucrose or lactose, lecithin, pectin, starch (eg corn starch or amylose), cyclodextrins and cyclodextrin derivatives, dextran, polyvinyl pyrrolidone, polyvinyl Acetate, gum arabic, alginic acid, xylose, talc, salicylic acid, calcium hydrogen phosphate, cellulose, cellulose derivatives (eg methylcellulose, methoxypropylcellulose, hydroxypropylmethylcellulose, and hydroxypropylmethylcellulose phthalate, fatty acids having 12 to 22 carbon atoms , Emulsifiers, oils and fats, especially vegetable glycerol esters and polyglycerol esters of saturated fatty acids, monohydric alcohols, polyhydric alcohols, polyethylene Polyglycols such as glycols, aliphatic alcohols having 1 to 20 carbon atoms, or polyhydric alcohols such as glycols, glycerol, diethylene glycol, 1,2-propylene glycol, sorbitol, mannitol, 2 to 2 carbon atoms There are 22 aliphatic saturated or unsaturated fatty acid esters.

  Other suitable adjuvants include disintegrants. Examples of disintegrants are cross-linked polyvinyl pyrrolidone, sodium carboxymethyl starch, sodium carboxymethyl cellulose, and microcrystalline cellulose. Coatings commonly used in the art can also be used. Examples include acrylic acid and / or methacrylic acid and / or ester polymers and copolymers thereof, zein, ethyl cellulose, ethyl cellulose succinate, shellac and the like.

  Plasticizers suitable as coating agents are citrate and tartaric acid esters, glycerol and glycerol esters, polyethylene glycols of various chain lengths.

  Liquid compositions such as solutions and suspensions are formulated in water or physiologically acceptable organic solvents, such as alcohols and fatty alcohols.

  In liquid pharmaceutical compositions, such as potassium solvate, preservatives such as methyl 4-hydroxybenzoate or propyl 4-hydroxybenzoate, antioxidants such as ascorbic acid, and peppermint oil A fragrance can be further included.

  In addition, when formulating liquid pharmaceutical compositions, conventional solubilizers or emulsifiers such as polyvinylpyrrolidone and polysorbate 80 may be used.

  Other examples of suitable excipients and adjuvants are disclosed in Dr. H.P. Fielder, “Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete” [Encyclopaedia of auxiliaries for pharmacy, cosmetics and related fields].

  Hereinafter, the present invention will be described more specifically with reference to examples. However, the following examples are provided for illustrative purposes only, and the present invention is not limited thereby.

4-メタンスルホニル安息香酸1gに4-メトキシフェニル酢酸エチルエステル970mg、及びカルボニルジイミダゾール950mgをジメチルホルムアミド15mlに溶解した後、水素化ナトリウム230mgを溶液に滴加し、混合物を常温で12時間反応させた。その後、水を加えて反応物を希釈し、酢酸エチルで抽出した。得られた有機層を、無水硫酸マグネシウムで乾燥させ、標記化合物を薄黄色の液体（1.5g）として得た（収率83％）。

Example 1
3- (4-Methanesulfonylphenyl) -2- (4-methoxyphenyl) -3-oxo-propionic acid ethyl ester

After dissolving 970 mg of 4-methoxyphenylacetic acid ethyl ester and 950 mg of carbonyldiimidazole in 15 ml of dimethylformamide in 1 g of 4-methanesulfonylbenzoic acid, 230 mg of sodium hydride is added dropwise to the solution, and the mixture is reacted at room temperature for 12 hours. It was. The reaction was then diluted with water and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate to obtain the title compound as a pale yellow liquid (1.5 g) (yield 83%).

4-メトキシフェニル酢酸エチルエステルの代わりに4-メトキシフェニル酢酸メチルエステル750mgを使用したことを除いては、実施例1と同様に標記化合物1.3g（収率80％）を液体として調製した。

Example 2
Preparation of 3- (4-methanesulfonylphenyl) -3-oxo-2-phenylpropionic acid methyl ester

1.3 g (yield 80%) of the title compound was prepared as a liquid in the same manner as in Example 1 except that 750 mg of 4-methoxyphenylacetic acid methyl ester was used instead of 4-methoxyphenylacetic acid ethyl ester.

4-メトキシフェニル酢酸エチルエステルの代わりに4-メチルフェニル酢酸エチルエステル0.89mgを使用したことを除いては、実施例1と同様に標記化合物1.5g（83％）を液体として調製した。

Example 3
3- (4-Methanesulfonylphenyl) -3-oxo-2- (4-methylphenyl) propionic acid ethyl ester

1.5 g (83%) of the title compound was prepared as a liquid in the same manner as in Example 1 except that 0.89 mg of 4-methylphenylacetic acid ethyl ester was used instead of 4-methoxyphenylacetic acid ethyl ester.

4-メトキシフェニル酢酸エチルエステルの代わりに(3,4-ジクロロフェニル)酢酸エチルエステル1.1gを使用したことを除いては、実施例１と同様に標記化合物1.7g（85％）を液体として調製した。

Example 4
2- (3,4-Dichlorophenyl) -3- (4-methanesulfonylphenyl) -3-oxo-propionic acid ethyl ester

1.7 g (85%) of the title compound was prepared as a liquid as in Example 1, except that 1.1 g of (3,4-dichlorophenyl) acetic acid ethyl ester was used instead of 4-methoxyphenylacetic acid ethyl ester. .

3-(4-メタンスルホニルフェニル)-2-(4-メトキシフェニル)-3-オキソ-プロピオン酸エチルエステルをトルエン20mlに溶解した後、ジメチルヒドラジン0.24gを溶液に加えた。ディーン−スタークトラップ装置において、混合物を含む装置を120℃で24時間加熱及び還流させた。反応混合物を冷却し、水で希釈した後、酢酸エチルで抽出した。得られた有機層は無水硫酸マグネシウムで乾燥させた後、減圧下で濃縮した。生成物をn-へキサンで再結晶させ、標記化合物160mgを黄色固体として得た（収率53％）。

FAB Mass(M+1)：373
IR:(υC=O) 1637cm^-1
融点：245〜247℃ Example 5
5- (4-Methanesulfonylphenyl) -4- (4-methoxyphenyl) -1,2-dimethyl-1,2-dihydropyrazol-3-one

After 3- (4-methanesulfonylphenyl) -2- (4-methoxyphenyl) -3-oxo-propionic acid ethyl ester was dissolved in 20 ml of toluene, 0.24 g of dimethylhydrazine was added to the solution. In the Dean-Stark trap apparatus, the apparatus containing the mixture was heated and refluxed at 120 ° C. for 24 hours. The reaction mixture was cooled, diluted with water and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The product was recrystallized from n-hexane to obtain 160 mg of the title compound as a yellow solid (yield 53%).

FAB Mass (M + 1): 373
IR: (υC = O) 1637cm ^-1
Melting point: 245-247 ° C

3-(4-メタンスルホニルフェニル)-2-(4-メトキシフェニル)-3-オキソ-プロピオン酸エチルエステルの代りに3-(4-メタンスルホニルフェニル)-3-オキソ-2-フェニルプロピオン酸メチルエステル0.3gを使用したことを除いては、実施例5と同様に標記化合物170mg（収率56％）を調製した。

EI Mass(M+)：342
IR:(υC=O) 1640cm^-1
融点：210〜212℃ Example 6
5- (4-Methanesulfonylphenyl) -1,2-dimethyl-4-phenyl-1,2-dihydropyrazol-3-one

Methyl 3- (4-methanesulfonylphenyl) -3-oxo-2-phenylpropionate instead of ethyl 3- (4-methanesulfonylphenyl) -2- (4-methoxyphenyl) -3-oxo-propionate 170 mg (yield 56%) of the title compound was prepared in the same manner as in Example 5 except that 0.3 g of ester was used.

EI Mass (M +): 342
IR: (υC = O) 1640cm ^-1
Melting point: 210-212 ° C

3-(4-メタンスルホニルフェニル)-2-(4-メトキシフェニル)-3-オキソ-プロピオン酸エチルエステルの代りに3-(4-メタンスルホニルフェニル)-3-オキソ-2-(4-メチルフェニル)プロピオン酸エチルエステル0.3gを使用したことを除いては、実施例5と同様に標記化合物180mg（収率60％）を調製した。

EI Mass(M+)：356
IR：(υC=O) 1626cm^-1
融点：247〜249℃ Example 7
5- (4-Methanesulfonylphenyl) -1,2-dimethyl-4- (4-methylphenyl) -1,2-dihydropyrazol-3-one

3- (4-Methanesulfonylphenyl) -2-oxo-4- (4-methyl) instead of 3- (4-methanesulfonylphenyl) -2- (4-methoxyphenyl) -3-oxo-propionic acid ethyl ester 180 mg (yield 60%) of the title compound was prepared in the same manner as in Example 5 except that 0.3 g of phenyl) propionic acid ethyl ester was used.

EI Mass (M +): 356
IR: (υC = O) 1626cm ^-1
Melting point: 247-249 ° C

3-(4-メタンスルホニルフェニル)-2-(4-メトキシフェニル)-3-オキソ-プロピオン酸エチルエステルの代りに2-(3,4-ジクロロフェニル)-3-(4-メタンスルホニルフェニル)-3-オキソ-プロピオン酸エチルエステル0.3gを使用したことを除いては、実施例5と同様に標記化合物190mg（収率57％）を調製した。

EI Mass(M+)：411
IR：(υC=O) 1637cm^-1
融点：240〜242℃ Example 8
4- (3,4-Dichlorophenyl) -5- (4-methanesulfonylphenyl) -1,2-dimethyl-1,2-dihydropyrazol-3-one

2- (3,4-dichlorophenyl) -3- (4-methanesulfonylphenyl)-instead of 3- (4-methanesulfonylphenyl) -2- (4-methoxyphenyl) -3-oxo-propionic acid ethyl ester 190 mg (57% yield) of the title compound was prepared in the same manner as in Example 5 except that 0.3 g of 3-oxo-propionic acid ethyl ester was used.

EI Mass (M +): 411
IR: (υC = O) 1637cm ^-1
Melting point: 240-242 ° C

Experimental example
1． Evaluation of selective COX-2 inhibitory activity
1) Method In order to determine the selective COX-2 inhibitory activity pharmacologically, the COX-1 and COX-2 inhibition rates of the compounds of the present invention exemplified in the Examples were measured by the following method.

a. Assay method of COX-1 inhibitory activity using U-937
U-937 human lymphoma cells (Korean Cell Line Bank, Seoul, Korea, deposit number: 21593) were cultured and centrifuged. The collected cells were diluted to a concentration of 1 × 10 ⁶ cells / ml using HBSS (1 ×, Hank's balanced salt solution). 1 ml of diluted cell solution was dispensed into each well of a 12-well plate. 5 μl of 1 μM DMSO solution of test compound and 5 μl DMSO as a control were added to the wells. The wells were incubated for 15 minutes at 37 ° C. in a CO ₂ incubator. Separately, a 10 mM stock solution of arachidonic acid dissolved in ethanol was diluted 10-fold with ethanol to prepare a 1 mM solution of arachidonic acid. Arachidonic acid acts as a substrate. 10 μl of 1 mM arachidonic acid solution was added to each well and incubated at 37 ° C. for 30 minutes in a CO ₂ incubator. The cell solution in each well was placed in a centrifuge tube and centrifuged at 4 ° C. and 10,000 rpm for 5 minutes. The concentration of PGE2 present in the collected cells and supernatant was quantified using a monoclonal kit (Cayman Chemicals). The PGE2 inhibition rate of the test compound-treated cell group relative to the DMSO-treated cell group was calculated. Based on the calculated value, COX-1 inhibitory activity was evaluated.

b. COX-2 inhibitory activity assay using RAW 264.7 cell line
The RAW 264.7 cell line (Korean Cell Line Bank, Seoul, Korea, deposit number: 40071) was inoculated 2 × 10 ⁶ cells in each well of a 12-well plate. Each well was treated with 250 μM aspirin and incubated at 37 ° C. for 2 hours. After the medium was replaced with fresh medium, the new medium was treated with the test compound (10 nM) and incubated for 30 minutes. Each well was then treated with interferon gamma (100 units / ml) and lipopolysaccharide (LPS, 100 ng / ml) and incubated for 18 hours. The medium was transferred to another test tube. The PGE2 concentration was quantified using an EIA kit (Cayman Chemicals).

2) Test results The test results are shown in Table 1 below. The COX inhibition rate was calculated by the following formula.
% Inhibition = (PGE2 concentration of test compound untreated sample−PGE2 concentration of test compound treated sample) / (PGE2 concentration of test compound untreated sample) × 100

(Table 1) Cyclooxygenase (COX) inhibition (%)

3) Evaluation
The results of in vitro tests on the inhibition rates of COX-1 and COX-2 are listed in Table 1.

  As shown in Table 1, the ratio of inhibition (%) of COX-2 to COX-1 in Examples 5 to 7 was significantly higher than the reference (valdecoxib). This indicates that the selective inhibition of COX-2 over COX-1 by the compounds of the present invention is superior to the reference.

  In addition, the compounds of Examples 5 to 7 showed significantly higher COX-2 inhibitory activity than the reference. Based on this result, it can be considered that the compound of the present invention has reduced side effects due to the enhanced selectivity and improved fever, pain, and inflammation alleviation compared to the reference.

INDUSTRIAL APPLICABILITY As is apparent from the above description, the present invention relates to a pyrazol-3-one derivative or a non-toxic salt thereof, a preparation method thereof, and a pharmaceutical composition containing the derivative or a salt thereof as an active ingredient Offer things. The pharmaceutical composition of the present invention is effective in reducing fever, pain, and inflammation. In particular, as a result of the reduced side effects of conventional non-steroidal anti-inflammatory agents, the pharmaceutical composition is useful for peptic ulcer disease, gastritis, localized enteritis, ulcerative colitis, diverticulitis, gastric bleeding, or low prothrombin Useful for the treatment of patients with septicemia.

  While the invention has been particularly shown and described with reference to exemplary embodiments thereof, those skilled in the art will recognize that the embodiments and forms do not depart from the spirit and scope of the invention as defined in the claims. It will be understood that various changes in detail may be made to the invention.

Claims (9)

A pyrazol-3-one derivative represented by Chemical Formula 1 or a non-toxic salt thereof:

Where
R ₁ and R ₂ each independently represent C ₁ -C ₃ alkyl, aryl, or substituted aryl;
R ₃ represents amino or methyl,
R ₄ and R ₅ each independently represent hydrogen, C ₁ -C ₃ alkyl, halogen, halogen-substituted methyl, C ₁ -C ₃ alkoxy, cyano, or nitro. R ₁ and R ₂ each independently represent C ₁ -C ₃ alkyl, R ₃ is methyl, and R ₄ and R ₅ are each independently hydrogen, C ₁ -C ₃ alkyl, halogen, or C it is ₁ -C ₃ alkoxy, pyrazol-3-one derivative or a non-toxic salt according to claim 1, wherein. 5- (4-methanesulfonylphenyl) -4- (4-methoxyphenyl) -1,2-dimethyl-1,2-dihydropyrazol-3-one;
5- (4-methanesulfonylphenyl) -1,2-dimethyl-4-phenyl-1,2-dihydropyrazol-3-one;
5- (4-methanesulfonylphenyl) -1,2-dimethyl-4- (4-methylphenyl) -1,2-dihydropyrazol-3-one; and
The pyrazole according to claim 1, selected from the group consisting of 4- (3,4-dichlorophenyl) -5- (4-methanesulfonylphenyl) -1,2-dimethyl-1,2-dihydropyrazol-3-one. -3-one derivatives or non-toxic salts thereof. Propionic acid derivative represented by Chemical Formula 4:

In which R ₃ , R ₄ and R ₅ are as defined in claim 1 and R ₆ represents C ₁ -C ₃ alkyl. A method for preparing a pyrazol-3-one derivative of Formula 1 or a non-toxic salt thereof comprising the step of reacting a hydrazine derivative of Formula 5 with a propionic acid derivative of Formula 4:

In which R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are as defined in claim 1 and R ₆ represents C ₁ -C ₃ alkyl. 6. The preparation method according to claim 5, wherein the propionic acid derivative of Chemical Formula 4 is prepared by reacting a sulfonylbenzoic acid derivative of Chemical Formula 2 with a phenyl acetate derivative of Chemical Formula 3 in the presence of a base:

In which R ₃ , R ₄ and R ₅ are as defined in claim 1 and R ₆ represents C ₁ -C ₃ alkyl.   Fever, pain, inflammation comprising a therapeutically effective amount of the pyrazol-3-one derivative or non-toxic salt thereof according to any one of claims 1 to 3 as an active ingredient, and a pharmaceutically acceptable carrier A pharmaceutical composition for the treatment of.   A therapeutically effective amount of the pyrazol-3-one derivative or non-toxic salt thereof according to any one of claims 1 to 3 as an active ingredient, and a pharmaceutically acceptable carrier, for treating cancer. Pharmaceutical composition.   A therapeutically effective amount of the pyrazol-3-one derivative or non-toxic salt thereof according to any one of claims 1 to 3 as an active ingredient, and a pharmaceutically acceptable carrier, for treating dementia. Pharmaceutical composition.